Benzimidazole compounds, such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, and gastro esophageal reflux disorders. Benzimidazole compounds effectively inhibit gastric acid secretion.
U.S. Pat. No. 4,255,431 discloses omeprazole and therapeutically acceptable salts thereof. The advantages of providing the salts of omeprazole and particularly the magnesium salt are disclosed in U.S. Pat. No. 4,738,974.
The single isomers of omeprazole are reported to be more useful in therapy when compared to the racemic omeprazole. U.S. Pat. No. 5,877,192 discloses the use of the (−)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, in the treatment of gastric acid related diseases as a means to decrease inter-individual variation in plasma levels compared to omeprazole. The use of the (−)-enantiomer of omeprazole to receive increased average plasma levels (AUC) of the substance compared to those of racemic omeprazole and thereby a higher dose efficiency is also disclosed in the patent.
U.S. Pat. No. 5,900,424 discloses omeprazole magnesium salt as having a degree of crystallinity that is higher than 70% as determined by x-ray powder diffraction. The patent teaches that the isolation and purification in full manufacturing scale of the magnesium omeprazole salt as per U.S. Pat. No. 4,738,974 presents a major problem. The magnesium omeprazole salt crystals so obtained by this method are very fragile. The patent further teaches that in order to use the magnesium salt of omeprazole in full manufacturing scale in preparing pharmaceutical formulations primarily for oral administration, such as tablets, it is necessary that the magnesium omeprazole possess a combination of properties. This makes such full scale manufacturing feasible. These physical properties include degree of crystallinity, particle diameter, density, hygroscopicity, water content and content of other solvents. U.S. Pat. No. 5,690,960 teaches stable oral formulation comprising a core containing a magnesium salt of omeprazole wherein the salt has more than 70% crystallinity as determined by x-ray powder diffraction; a subcoating layer; and an enteric coating layer.
The efforts to stabilize benzimidazole compositions using amorphous form of benzimidazole compounds are reported in prior art. WO 2004/037253, assigned to Ranbaxy Laboratories and WO 2004/002982, assigned to Dr. Reddy's Laboratories teach processes of preparing amorphous forms of a salt of esomeprazole.
U.S. Pat. No. 6,713,495 discloses magnesium omeprazole having a degree of crystallinity of less than 67% by weight and having a residual organic solvent content of less than 7% by weight. U.S. Patent Application No. 2003/0232861 discloses magnesium s-omeprazole having a degree of crystallinity of less than 67%. Example 3 of U.S. Pat. No. 6,713,495 and U.S. Patent Application No. 2003/0232861 disclose magnesium omeprazole and magnesium esomeprazole respectively, having a degree of crystallinity less than 25%.
Indian Application No. 1494/DEL/2003, assigned to Ranbaxy Laboratories, discloses stable oral benzimidazole compositions. The compositions include a core comprising amorphous or crystalline benzimidazole compound, a substantially water-insoluble and substantially non-disintegrating separating layer and an enteric coating.
U.S. Patent Application No. 2002/0128293 teaches stable oral pharmaceutical compositions that include omeprazole and a stabilizing excipient, wherein the composition is free of alkaline compounds. Example 7 of the patent application discloses a process of wet drug layering of an inert carrier using a Wurster fluid bed apparatus.
Because of the strong tendency of benzimidazole compounds to decompose in a neutral and in particular, an acidic environment, numerous approaches have been tried to form a stable pharmaceutical formulation comprising such compounds. The acid labile benzimidazole compounds react with both the gastric acid in the stomach and the enteric coatings used for preventing the benzimidazole compound from coming into contact with the gastric acid.
The prior art teaches various approaches to prepare the stable formulations containing benzimidazole compounds. Amongst the most common approaches to stabilize benzimidazole is the use of an alkaline core, separating layer and enteric coating. It is a well-recognized fact that using an alkaline medium in the core stabilizes benzimidazole from acid degradation. Prior art efforts to stabilize a benzimidazole with an alkaline core without a separating layer between the core and the enteric coating was not effective. Thus the recognition of using a layer to separate the alkaline core from the acidic enteric coating was the subject matter of U.S. Pat. No. 4,786,505 and U.S. Pat. No. 4,853,230. The separating coating disclosed in these patents was essentially made up of water-soluble polymeric substances.
U.S. Pat. Nos. 6,274,173; 6,602,522; 5,385,739; 5,626,875; 6,159,499 and 6,207,198 disclose various other formulation approaches to stabilize benzimidazole compositions.
However, there is still a need for the development of new pharmaceutical compositions of benzimidazole compounds with enhanced stability. It was surprisingly observed that careful control of some of the processing parameters is critical to prevent the conversion of the amorphous form of benzimidazole compound to the crystalline form.
The present invention thus relates to the stable oral amorphous benzimidazole compositions and process for preparing the same as herein below described and exemplified.